Lactic acidosis in man is a relatively common disease with a generally poor prognosis. It is a condition commonly associated with diabetes mellitus in man. Significant advancements in the treatment of this disorder have not been accomplished, and this is partially due to the lack of knowledge of the pathophysiologic mechanisms which are involved. The studies outlined in this proposal are designed to examine the pathophysiology and treatment of this disease in an in vivo animal model of lactic acidosis developed in diabetic dogs. In this model, the pathophysiologic studies will evaluate the respective roles and possible mechanisms of increased lactate production and impaired lactate utilization as causes of lactate acidosis. Such studies will quantitate the net flux of lactate and other substrates in tissues such as skeletal muscle, gut, brain, and liver during experimental lactic acidosis. Additional studies will report the roles of intracellular redox states and intracellular pH in the pathogenesis of the altered lactate metabolism in these tissues. Studies on the treatment of experimental lactic acidosis will evaluate the efficacy of sodium bicarbonate and sodium dichloroacetate in improving the abnormalities found in this model. Results from these studies may provide information which will improve the knowledge and treatment of lactic acidosis in man.